Analysis of norepinephrine-regulated cerebral lymphatic drainage by the second near-infrared region in vivo imaging

The cerebral lymphatic drainage plays an important role in the occurrence and development of central nervous system diseases. Recent studies have shown that cerebral lymphatic drainage is regulated by circadian rhythm and anesthesia state; however, the regulating mechanism is still unclear. In this study, we used the second near-infrared region in vivo imaging to explore the regulation of cerebral lymphatic drainage in mice at different states. At first, by injection of a tracer at different times, we confirmed that the drainage of the meningeal lymphatic system was the fastest at zeitgeber time 2, while the internal flow of the glymphatic system was the slowest. Under anesthesia with isoflurane, administration of dexmedetomidine, an anesthetic that inhibits norepinephrine (NE) release, enabled mice to enter the stage of non-rapid eye movement sleep, at which time the influx of the glymphatic system increased, the efflux of the meningeal lymphatic system decreased, and the clearance rate of the brain parenchyma decreased. However, following the exogenous NE supplement, mice quickly changed from a non-rapid eye movement stage into an awake state with the meningeal lymphatic drainage retrieval. The results showed whether the drainage of the glymphatic system and meningeal lymphatic vessels, or parenchymal clearance, has made rapid adjustments based on sleep status that is regulated by NE. This study reveals that the NE-regulated sleep–wake cycle is a powerful regulator of cerebral lymphatic drainage and provides a potential therapeutic target for related central nervous system diseases.